Aminocyclopentadienyl ruthenium complexes and preparation thereof

ABSTRACT

Novel aminocyclopentadienyl ruthenium complex is useful as a catalyst in the racemization of a chiral compound.

FIELD OF THE INVENTION

The present invention relates to a novel ruthenium complex which is aremarkably effective catalyst in the racemization of chiral compounds.

BACKGROUND OF THE INVENTION

The production of one enantiomeric form of a chiral compound is oftenrequired in the pharmaceutical and other chemical industries and thedesired enantiomer is obtained via resolution of its racemate. In such aprocess it is essential from the economic point of view to convert theunwanted enantiomer back to the racemic form and recycled.

In the racemization step, ruthenium complexes such as [(p-cymene)RuCl₂]₂and (η⁵-Ph₄C₄CO)₂H(μ-H)(CO)₄Ru₂ (Shvo catalyst) are used as a catalyst.However, the ruthenium cymene complex exhibits a slow racemizationreaction at room temperature, and Shvo catalyst which exists in the formof a dimer must be activated at a high temperature and it also requiresthe use of a hydrogen-transfer agent, e.g., the corresponding ketone tothe alcohol in case a chiral alcohol is to be racemized (Y. Shvo et al,Organometallics, 8, 162, 1989).

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a novelcompound which can be used as an effective catalyst in the racemizationof chiral alcohols under a mild condition.

It is another object of the present invention to provide a process forthe preparation of said compound.

In accordance with one aspect of the present invention, there isprovided a ruthenium complex of formula(I):

wherein:

-   -   R¹, R², R³ and R⁴ are each independently phenyl, substituted        phenyl or C₁₋₅alkyl;    -   R⁵ is hydrogen, phenyl, substituted phenyl, C₁₋₅alkyl,        substituted C₁₋₅alkyl, C₃₋₇cycloalkyl, C₂₋₅alkenyl or        C₂₋₅alkynyl; and    -   X, Y and Z are each independently hydrogen, halogen, carbonyl or        PR⁵ ₃.

Further, in accordance with another aspect of the present invention,there is provided a process for the preparation of the ruthenium complexof Formula(I), which comprises reacting a compound of Formula(II) and aruthenium compound, such as Ru₃(CO)₁₂, RuCl₂(CO)₂(PR⁵ ₃)₂,[RuCl₂(CO)₃]₂, RuCl₂(PR⁵ ₃)₃, and RuCl₃ in a solution containing ahaloform:

wherein:

-   -   R¹, R², R³, R⁴ and R⁵ have the same meanings as defined above.

DETAILED DESCRIPTION OF THE INVENTION

In the compound of Formula(I) of the present invention, the substituentof the substituted phenyl is at least one selected from the groupconsisting of C₁₋₅alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, halogen,nitro, nitroso, amino, aminocarbamyl, hydroxy, mercapto andC₁₋₅alkylthio, and the substituent of the substituted C₁₋₅alkyl is atleast one selected from the group consisting of aryl, C₁₋₅alkoxy,halogen, nitro, nitroso, amino, aminocarbamyl, hydroxy, mercapto andC₁₋₅alkylthio.

In Formula(I) of the present invention, R¹, R², R³ or R⁴ is preferably aphenyl or C₁₋₅alkyl group, R⁵ is preferably hydrogen, a phenyl orsubstituted phenyl group, a C₁₋₅alkyl or substituted C₁₋₅alkyl group ora C₃₋₇cycloalkyl group, and X, Y and Z substituents are each preferablyhydrogen, halogen, carbonyl, or a phosphine group.

The ruthenium complex of Formula(I) of the present invention may beprepared according to Reaction Scheme A:

wherein:

-   -   R¹, R², R³, R⁴, R⁵, X, Y and Z have the same meanings as defined        in formula(I) above.

Namely, a cyclopentadienone derivative such astetraphenylcyclopentadienone is reacted in an aprotic solvent with aprimary amine in the presence of a Lewis acid to obtain an iminecompound of Formula(II)(Step 1). Then, the imine compound of Formula(II)is reacted with a ruthenium compound having X, Y and Z groups, such asRu₃(CO)₁₂, RuCl₂(CO)₂(PR⁵ ₃)₂, [RuCl₂(CO)₃]₂, RuCl₂(PR⁵ ₃)₃, or RuCl₃ ina solvent, preferably a haloform to obtain the ruthenium complex ofFormula(I) of the present invention(Step 2).

Representative examples of the primary amine used in Step 1 are ammonia,methylamine, ethylamine, propylamine, butylamine, pentylamine,isobutylamine, isopropylamine, t-butylamine, cyclopropylamine,cyclobutylamine, cyclopentylamine, aniline, toluidine and benzylamine.Also used in the present invention is a conventional Lewis acid,commonly known in the art, including TiCl₄, AlCl₃, BF₃ and SnCl₄.

Representative examples of the aprotic solvent are toluene, benzene,hexane, oxane, tetrahydrofuran, diethyl ether, diisopropyl ether,t-butylmethyl ester, ethyl acetate, acetonitrile, acetone,dichloromethane, chloroform and carbon tetrachloride.

In Step 1, the primary amine, the Lewis acid and the aprotic solvent maybe used in amounts of 1 to 7 molar equivalents, 0.1 to 3 molarequivalents and 2 to 20 folds (v/v), respectively, based on the startingcyclopentadienone derivative, and the reaction may be conducted at atemperature in the range of 50° C. to 150° C.

In Step 2, the solvent may be chloroform, bromoform or fluoroform, andthe amount of the imine compound of Formula(II) may be 1 to 3 moleequivalents based on the ruthenium compound. The reaction may beconducted at a temperature in the range of 40° C. to 120° C.

The ruthenium complex of Formula(I) of the present invention is usefulparticularly in the racemization reaction of a secondary alcohol. Theracemization may be carried out by adding the complex of Formula(I) ofthe present invention, together with a base, to a secondary alcoholhaving a chiral center in an aprotic solvent and agitating the resultingmixture at room temperature for about 30 minutes under an inertatmosphere. The base may be an inorganic base such as LiOH, KOH, NaOH,tBuOK and Na₂CO₃ or an organic base such as triethylamine,diisopropylethylamine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN(1,5-diazabicyclo[4.3.0]non-5-ene), while the aprotic solvent may betoluene, hexane, benzene, tetrahydrofuran, dioxane, dialkyl ether, alkylacetate, acetonitrile, acetone, dichloromethane, chloroform or carbontetrachloride. As the solvent, a water-immiscible alcohol having four ormore carbon atoms may also be used.

In the racemization reaction, the complex of Formula(I) of the presentinvention and the base may be used in amounts of 10⁻⁶ to 0.05 and 10⁻⁶to 0.06 equivalent amounts, respectively, based on the chiral compoundto be racemized.

The following Examples are included to further illustrate the presentinvention without limiting its scope.

Systhesis of Ruthenium Complexes

EXAMPLE 1 Synthesis ofN-isobutylamino-2,3,4,5-tetraphenylcyclopentadienyl ruthenium dicarbonylchloride

Step 1) Synthesis of N-isobutyl-2,3,4,5-tetraphenylcyclopentadieneimine

3 g (7.8 mmol) of tetraphenylcyclopentadienone and 3.49 ml (35.1 mmol)of isobutylamine were dissolved in 50 ml of toluene and 0.7 ml(5.85mmol) of TiCl₄ was added thereto at 0° C. The resulting mixture wasagitated for 30 minutes at room temperature and then refluxed for 12hours. The reaction mixture was cooled and ether was added thereto toinduce solid precipitation. The resultant solid was filtered and driedto obtain 2.3 g of the title compound.

m.p.: 158C; ¹H NMR(CDCl₃): 7.25-7.18 (m, 10H), 7.09-7.00(m, 6H), 6.85(d,J=6.6 Hz, 2H), 6.78(m, J=6.6 Hz, 2H), 3.36(d, J=6.5 Hz, 8H), 1.83(m,1H), 0.79(d, J=6.6 Hz, 2H)

Step 2) Synthesis of N-isobutylamino-2,3,4,5-tetraphenylcyclopentadienylruthenium dicarbonyl chloride

1 g (2.4 mmol) of the compound prepared in Step 1 and 1 g (1.6 mmol) ofRu₃(CO)₁₂ were dissolved in 8 ml of chloroform and reacted under anargon atmosphere at 90° C. for 5 days. The reaction mixture was cooled,concentrated and the residue was purified by column chromatography(column: silica gel, eluent: from hexane/ethylacetate of 8:1 todichloromethane; gradient) to obtain 0.7 g of the title compound

m.p.: 151˜152° C. (dec.); ¹H NMR(CDCl₃): 7.58-7.56(m, 4H), 7.38-7.33(m,6H), 7.09(dd, J=7.1 Hz, 2H), 7.02-7.91(m, 8H), 4.36(t, J=5.7 Hz, 1H),2.56(t, J=6.4, 2H), 1.39(m, 1H), 0.57(d, J=6.7 Hz, 6H); ¹³C NMR(CDCl₃):198.6, 144.1, 133.7, 132.1, 130.7, 130.6, 129.1, 128.9, 128.4, 127.9,101.6, 83.7, 52.1, 29.3, 20.1

EXAMPLE 2 Synthesis ofN-isopropylamino-2,3,4,5-tetraphenylcyclopentadienyl rutheniumdicarbonyl chloride

Step 1) Synthesis of N-isopropyl-2,3,4,5-tetraphenylcyclopentadieneimine

The procedure of Step1 of Example 1 was repeated using 2.1 g ofisopropylamine in place of isobutylamine to prepare the title compound.

m.p.: 223° C.; ¹H NMR(CDCl₃): 7.25-6.75 (m, 20H), 4.08-4.00 (m, 1H),1.04(d, J=3 Hz, 6H); ¹³C NMR(CDCl₃): 165.8, 137.6, 131.9, 130.2, 129.8,128.2, 127.8, 127.4, 127.2, 127.1, 126.5, 52.3, 24.3

Step 2) Synthesis ofN-isopropylamino-2,3,4,5-tetraphenylcyclopentadienyl rutheniumdicarbonyl chloride

The procedure of Step2 of Example 1 was repeated using the compoundprepared in Step1 to prepare the title compound.

m.p.: 197° C. (dec.); ¹H NMR(CDCl₃): 7.57-6.91(m, 20H), 4.20(d, J=4.1Hz, 1H), 3.3-3.23(m,1H), 0.86(d, J=3.2 Hz, 6H); ¹³C NMR(CDCl₃): 198.4,144.8, 133.7, 131.9, 130.6, 128.9, 128.7, 128.2, 127.7, 101.4, 81.7,45.6, 25.2

EXAMPLE 3 Synthesis ofN-isobutylamino-2,3,4,5-tetraphenylcyclopentadienyl ruthenium dicarbonylhydride

90 mg (0.14 mmol) of N-isopropyl-2,3,4,5-tetrabutylcyclopentadienylruthenium dicarbonyl chloride prepared in Example 1 and 45 mg (0.42mmol) of sodium carbonate were dissolved in 6 ml of isopropanol andreacted at 90° C. for 5 hours. The reaction mixture was filtered and thefiltrate was concentrated to prepare 83 mg of the title compound.

m.p.: 86.7° C. (dec.); ¹ H NMR(C₄D₆): 7.77(d, J=6.8 Hz, 4H),7.57-7.54(m, 4H), 7.22-7.16(m, 8H), 7.04-7.01(m, 6H), 3.17(t, J=6.9 Hz,1H), 2.66(t, J=6.5 Hz, 2H), 1.49(m, 1H), 0.82(d, J=6.5 Hz, 6H); ¹³CNMR(C₆D₆): 203.6, 133.9, 133.7, 132.9, 131.7, 129.2, 129.0, 128.7,106.6, 92.1, 61.2, 29.2, 20.8

EXAMPLE 4 Synthesis ofN-isopropylamino-2,3,4,5-tetraphenylcyclopentadienyl rutheniumdicarbonyl hydride

The procedure of Example 3 was repeated usingN-isopropyl-2,3,4,5-tetrapropylcyclopentadienyl ruthenium dicarbonylchloride prepared in Example 2 to prepare the title compound.

m.p.: 140° C. (dec.); ¹H NMR(C₆D₆): 7.57-6.73(m, 20H), 2.99-2.93(m, 1H),2.57(d, J=4.6 Hz, 1H),-9.14(s, 1H); ¹³C NMR(C₆D₆): 203.6, 134.1, 133.4,132.9, 132.8, 130.2, 129.0, 127.8, 127.1, 106.3, 91.0, 50.1, 21.9

Racemization of Chiral Secondary Alcohol Using Ruthenium Complexes ofthe Present Invention

EXAMPLE 5

1 mg of potassium t-butoxide, 6 mg ofN-isobutylamino-2,3,4,5-tetrabutylcyclopentadienyl ruthenium dicarbonylchloride prepared in Example 1 and 30 μl of (S)-1-phenylethanol (>99%ee) were dissolved in 1 ml of toluene and was agitated at roomtemperature for 30 minutes under an argon atmosphere. The reactionmixture was filtered and the filtrate was concentrated. The opticalpurity of the product measured with a HPLC(High Performance LiquidChromatograph) equipped with a chiral column was 2% ee.

EXAMPLE 6

0.5 μl of 0.5 M Na₂CO₃, 6mg ofN-isobutylamino-2,3,4,5-tetraphenylcyclopentadienyl ruthenium dicarbonylhydride prepared in Example 3 and 30 μl of (S)-1-phenylethanol (>99% ee)were dissolved in 1 ml of toluene and the procedure of Example 5 wasrepeated. The optical purity after the reaction was 11% ee.

EXAMPLE 7

1 mg of potassium t-butoxide, 6 mg ofN-isopropylamino-2,3,4,5-tetraphenylcyclopentadienyl rutheniumdicarbonyl chloride prepared in Example 2 and 30μl of(S)-1-phenylethanol (>99% ee) were dissolved in 1 ml of one of thesolvents listed in Table 1 and agitated for 30 minutes at roomtemperature under an argon atmosphere. The optical purity measured as inExample 5 is shown in Table 1. TABLE 1 Solvent Reaction time(hours)Optical purity(% ee) Toluene 0.5 0.0 methylene chloride 0.5 0.0tetrahydrofuran 0.5 0.0 Acetone 0.5 24.7 toluene + vinyl 1.0 6.8 acetatemixture(22:1) No solvent 12.0 1.6

EXAMPLE 8

The procedure of Example 6 was repeated usingN-isopropylamino-2,3,4,5-tetraphenylcyclopentadienyl rutheniumdicarbonyl hydride prepared in Example 4. The optical purity after thereaction was 1.2% ee.

As the above results show, the ruthenium complexes of Formula(I)according to the present invention can racemize a chiral secondaryalcohol rapidly at room temperature in the absence of ahydrogen-transfer agent.

While the invention has been described with respect to the specificembodiments, it should be recognized that various modifications andchanges may be made by those skilled in the art to the invention whichalso fall within the scope of the invention as defined by the appendedclaims.

1. A ruthenium complex of Formula(I):

wherein: R¹, R², R³ and R⁴ are each independently phenyl, substitutedphenyl or C₁₋₅alkyl; R⁵ is hydrogen, phenyl, substituted phenyl,C₁₋₅alkyl, substituted C₁₋₅alkyl, C₃₋₇cycloalkyl, C₂₋₅alkenyl orC₂₋₅alkynyl; and X, Y and Z are each independently hydrogen, halogen,carbonyl or PR⁵ ₃.
 2. The ruthenium complex of claim 1, wherein thesubstituent of the substituted phenyl is at least one selected from thegroup consisting of C₁₋₅alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy,halogen, nitro, nitroso, amino, aminocarbamyl, hydroxy, mercapto andC₁₋₅alkylthio and the substituent of the substituted C₁₋₅alkyl is atleast one selected from the group consisting of aryl, C₁₋₅alkoxy,halogen, nitro, nitroso, amino, aminocarbamyl, hydroxy, mercapto andC₁₋₅alkylthio.
 3. The ruthenium complex of claim 1, wherein R¹, R², R³and R⁴ are each phenyl or C₁₋₅alkyl; R⁵ is hydrogen, phenyl, C₁₋₅alkylor C₃₋₇cycloalkyl; and X, Y and Z substituents are each independentlyhydrogen, halogen, carbonyl or phosphine.
 4. A process for thepreparation of the ruthenium complex of claim 1, which comprisesreacting a compound of Formula(II) and a ruthemium compound selectedfrom the group of Ru₃(CO)₁₂, RuCl₂(CO)₂(PR⁵ ₃)₂, [RUCl₂(CO)₃]₂,RuCl₂(PR⁵ ₃)₃, and RuCl₃ in a solution containing a haloform:

wherein: R¹, R², R³, R⁴ and R⁵ have the same meanings as defined inclaim
 1. 5. The process of claim 4, wherein the compound of Formula(II)is obtained by reacting a cyclopentadienone in an aprotic solvent in thepresence of a primary amine and a Lewis acid.
 6. The process of claim 4,wherein the primary amine, the Lewis acid and the aprotic solvent areused in amounts of 1 to 7 molar equivalents, 0.1 to 3 molar equivalentsand 2 to 20 folds (v/v), respectively, based on the compound ofFormula(II).
 7. The process of claim 6, wherein the reaction isconducted at a temperature in the range of 50° C. to 150° C.
 8. Theprocess of claim 4, wherein the compound of Formula(II) and theruthenium compound are used in a molar ratio ranging from 1:1 to 3:1. 9.The process of claim 4, wherein the reaction is conducted at atemperature in the range of 40° C. to 120° C.
 10. A process for theracemization of a chiral compound, which comprises reacting the chiralcompound with the complex of claim 1 in the presence of a base.
 11. Theprocess of claim 10, wherein the chiral compound is a secondary alcohol.